Cyclin D1 Regulates Cellular Migration through the Inhibition of Thrombospondin 1 and ROCK Signaling

ABSTRACT Cyclin D1 is overexpressed in human tumors, correlating with cellular metastasis, and is induced by activating Rho GTPases. Herein, cyclin D1-deficient mouse embryo fibroblasts (MEFs) exhibited increased adhesion and decreased motility compared with wild-type MEFs. Retroviral transduction of cyclin D1 reversed these phenotypes. Mutational analysis of cyclin D1 demonstrated that its effects on cellular adhesion and migration were independent of the pRb and p160 coactivator binding domains. Genomewide expression arrays identified a subset of genes regulated by cyclin D1, including Rho-activated kinase II (ROCKII) and thrombospondin 1 (TSP-1). cyclin D1 −/− cells showed increased Rho GTP and ROCKII activity and signaling, with increased phosphorylation of LIM kinase, cofilin (Ser3), and myosin light chain 2 (Thr18/Ser19). Cyclin D1 repressed ROCKII and TSP-1 expression, and the migratory defect of cyclin D1 −/− cells was reversed by ROCK inhibition or TSP-1 immunoneutralizing antibodies. cyclin E knockin to the cyclin D1 −/− MEFs rescued the DNA synthesis defect of cyclin D1 −/− MEFs but did not rescue either the migration defect or the abundance of ROCKII. Cyclin D1 promotes cellular motility through inhibiting ROCK signaling and repressing the metastasis suppressor TSP-1.

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Faculty Opinions recommendation of Cyclin D1 regulates cellular migration through the inhibition of thrombospondin 1 and ROCK signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1032961.374592 ◽

2006 ◽

Author(s):

Paul Bornstein

Keyword(s):

Cyclin D1 ◽

Cellular Migration ◽

Thrombospondin 1

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Faculty Opinions recommendation of PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13816956.15253056 ◽

2012 ◽

Author(s):

Stephen Lockett

Keyword(s):

Cyclin D1 ◽

Cellular Migration ◽

Splice Form ◽

Alternate Splice ◽

Direct Association

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Effects of a New Bioceramic Material on Human Apical Papilla Cells

Journal of Functional Biomaterials ◽

10.3390/jfb9040074 ◽

2018 ◽

Vol 9 (4) ◽

pp. 74 ◽

Cited By ~ 16

Author(s):

Diana Sequeira ◽

Catarina Seabra ◽

Paulo Palma ◽

Ana Cardoso ◽

João Peça ◽

...

Keyword(s):

Wound Healing ◽

Mineral Trioxide Aggregate ◽

Cellular Adhesion ◽

Cellular Migration ◽

Cellular Viability ◽

Migration Rates ◽

Apical Papilla ◽

And Migration ◽

Proliferation And Migration

Background: The development of materials with bioregenerative properties is critically important for vital pulp therapies and regenerative endodontic procedures. The aim of this study was to evaluate the cytocompatibility and cytotoxicity of a new endodontic biomaterial, PulpGuard, in comparison with two other biomaterials widely used in endodontic procedures, ProRoot Mineral Trioxide Aggregate (MTA) and Biodentine. Methods: Apical papilla cells (APCs) were isolated from third molars with incomplete rhizogenesis from patients with orthodontic indication for dental extraction. Cultured APCs were incubated for 24, 48, or 72 h with different dilutions of eluates prepared from the three materials. Cellular viability, mobility, and proliferation were assessed in vitro using the Alamar Blue assay and a wound-healing test. The cells were also cultured in direct contact with the surface of each material. These were then analyzed via Scanning Electron Microscopy (SEM), and the surface chemical composition was determined by Energy-Dispersive Spectroscopy (EDS). Results: Cells incubated in the presence of eluates extracted from ProRoot MTA and PulpGuard presented rates of viability comparable to those of control cells; in contrast, undiluted Biodentine eluates induced a significant reduction of cellular viability. The wound-healing assay revealed that eluates from ProRoot MTA and PulpGuard allowed for unhindered cellular migration and proliferation. Cellular adhesion was observed on the surface of all materials tested. Consistent with their disclosed composition, EDS analysis found high relative abundance of calcium in Biodentine and ProRoot MTA and high abundance of silicon in PulpGuard. Significant amounts of zinc and calcium were also present in PulpGuard discs. Concerning solubility, Biodentine and ProRoot MTA presented mild weight loss after eluate extraction, while PulpGuard discs showed significant water uptake. Conclusions: PulpGuard displayed a good in vitro cytocompatibility profile and did not significantly affect the proliferation and migration rates of APCs. Cells cultured in the presence of PulpGuard eluates displayed a similar profile to those cultured with eluates from the widely used endodontic cement ProRoot MTA.

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Minireview: Cyclin D1: Normal and Abnormal Functions

Endocrinology ◽

10.1210/en.2004-0959 ◽

2004 ◽

Vol 145 (12) ◽

pp. 5439-5447 ◽

Cited By ~ 621

Author(s):

Maofu Fu ◽

Chenguang Wang ◽

Zhiping Li ◽

Toshiyuki Sakamaki ◽

Richard G. Pestell

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Chromatin Remodeling ◽

Original Description ◽

Cellular Migration ◽

Regulatory Subunit ◽

Cyclin Dependent Kinase ◽

Fat Cell ◽

Independent Functions ◽

Cancer Côlon

Abstract Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein and promotes progression through the G1-S phase of the cell cycle. Amplification or overexpression of cyclin D1 plays pivotal roles in the development of a subset of human cancers including parathyroid adenoma, breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer. Of the three D-type cyclins, each of which binds cyclin-dependent kinase (CDK), it is cyclin D1 overexpression that is predominantly associated with human tumorigenesis and cellular metastases. In recent years accumulating evidence suggests that in addition to its original description as a CDK-dependent regulator of the cell cycle, cyclin D1 also conveys cell cycle or CDK-independent functions. Cyclin D1 associates with, and regulates activity of, transcription factors, coactivators and corepressors that govern histone acetylation and chromatin remodeling proteins. The recent findings that cyclin D1 regulates cellular metabolism, fat cell differentiation and cellular migration have refocused attention on novel functions of cyclin D1 and their possible role in tumorigenesis. In this review, both the classic and novel functions of cyclin D1 are discussed with emphasis on the CDK-independent functions of cyclin D1.

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Biological Mechanisms for Cartilage Repair Using a BioCartilage Scaffold: Cellular Adhesion/Migration and Bioactive Proteins

Cartilage ◽

10.1177/1947603519900803 ◽

2020 ◽

pp. 194760351990080 ◽

Cited By ~ 1

Author(s):

Jacqueline Commins ◽

Rebecca Irwin ◽

Andrea Matuska ◽

Margaret Goodale ◽

Michelle Delco ◽

...

Keyword(s):

Fibrin Glue ◽

Cartilage Repair ◽

Matrix Protein ◽

Cell Attachment ◽

Interleukin 1 ◽

Cellular Adhesion ◽

Cellular Migration ◽

Cartilage Explants ◽

Cartilage Defects ◽

Bioactive Proteins

Objective. BioCartilage is a desiccated, particulated cartilage allograft used for repair of focal cartilage defects. It is mixed with a biologic such as bone marrow concentrate (BMC), pressed into a contained defect, and sealed with fibrin glue. The objective of this study was to assess if BioCartilage could serve as a bioactive scaffold by affecting cellular adhesion, cellular migration, or the release interleukin-1 receptor antagonist protein (IL-1RA), and to identify its full proteomic makeup. Design. Cartilage explants were used to model confined defects. BioCartilage was mixed with BMC, grafted into defects, and sealed with 1 of 5 fibrin glues. Constructs were cultured for 24 or 48 hours and then processed for live/dead microscopy. Chondrocyte and mesenchymal stem cell (MSC) adhesion on BioCartilage was assessed using scanning electron microscopy. Conditioned medium from cultures and the biologics used in the study were assayed for IL-1RA. The protein footprint of BioCartilage was determined using bottom-up proteomics. Results. BioCartilage supported chondrocyte and MSC attachment within 24 hours, and cell viability was retained in all constructs at 24 and 48 hours. Fibrin glue did not inhibit cell attachment. BMC had the highest concentration of IL-1RA. Proteomics yielded 254 proteins, including collagens, proteoglycans, and several bioactive proteins with known anabolic roles including cartilage oligomeric matrix protein. Conclusions. This study suggests that BioCartilage has the chemical composition and architecture to support cell adherence and migration and to provide bioactive proteins, which together should have biologics advantages in cartilage repair beyond its role as a scaffold.

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Immunohistochemistry of cyclin D1 and β-catenin, and mutational analysis of exon 3 of β-catenin gene in parathyroid adenomas

International Journal of Oncology ◽

10.3892/ijo.20.3.463 ◽

2002 ◽

Author(s):

Satoshi Ikeda ◽

Yasuyo Ishizaki ◽

Yosuke Shimizu ◽

Masahiko Fujimori ◽

Yasutomo Ojima ◽

...

Keyword(s):

Cyclin D1 ◽

Mutational Analysis ◽

Parathyroid Adenomas

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RETRACTED: Nuclear Translocation of LIM Kinase Mediates Rho-Rho Kinase Regulation of Cyclin D1 Expression

Developmental Cell ◽

10.1016/s1534-5807(03)00206-5 ◽

2003 ◽

Vol 5 (2) ◽

pp. 273-284 ◽

Cited By ~ 41

Author(s):

Kristin Roovers ◽

Eric A Klein ◽

Paola Castagnino ◽

Richard K Assoian

Keyword(s):

Cyclin D1 ◽

Nuclear Translocation ◽

Rho Kinase ◽

Lim Kinase ◽

Kinase Regulation

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Expression of metastasis suppressor BRMS1 in breast cancer cells results in a marked delay in cellular adhesion to matrix

Molecular Carcinogenesis ◽

10.1002/mc.22068 ◽

2013 ◽

Vol 53 (12) ◽

pp. 1011-1026 ◽

Cited By ~ 9

Author(s):

Yekaterina B. Khotskaya ◽

Benjamin H. Beck ◽

Douglas R. Hurst ◽

Zhenbo Han ◽

Weiya Xia ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cellular Adhesion ◽

Metastasis Suppressor

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Thromboxane-induced actin polymerization in hypoxic pulmonary artery is independent of Rho

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00016.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. L13-L26 ◽

Cited By ~ 26

Author(s):

Jena Fediuk ◽

Alexey Gutsol ◽

Nora Nolette ◽

Shyamala Dakshinamurti

Keyword(s):

Rho Gtpases ◽

Laser Scanning ◽

Actin Polymerization ◽

Isometric Force ◽

Renal Arteries ◽

Force Generation ◽

Lim Kinase ◽

Thromboxane Receptor ◽

Laser Scanning Cytometry ◽

And Control

Actin polymerization (APM), regulated by Rho GTPases, promotes myocyte force generation. Hypoxia is known to impede postnatal disassembly of the actin cytoskeleton in pulmonary arterial (PA) myocytes. We compared basal and agonist-induced APM in myocytes from PA and descending aorta (Ao), under hypoxic and normoxic conditions. We also examined effects of thromboxane challenge on force generation and cytoskeletal assembly in resistance PA and renal arteries from neonatal swine with persistent pulmonary hypertension (PPHN) induced by 72-h normobaric hypoxia, compared with age-matched controls. Synthetic and contractile phenotype myocytes from neonatal porcine PA or Ao were grown in hypoxia (10% O2) or normoxia (21% O2) for 7 days, then challenged with 10−6 M thromboxane mimetic U46619. F/G actin ratio was quantified by laser-scanning cytometry and by cytoskeletal fractionation. Thromboxane receptor (TP) G protein coupling was measured by immunoprecipitation and probing for Gαq, G12, or G13, RhoA activation by Rhotekin-RBD affinity precipitation, and LIM kinase (LIMK) and cofilin phosphorylation by Western blot. Isometric force to serial concentrations of U46619 was measured in muscular pulmonary and renal arteries from PPHN and control swine; APM was quantified in fixed contracted vessels. Contractile PA myocytes exhibit marked Rho-dependent APM in hypoxia, with increased active RhoA and LIMK phosphorylation. Their additional APM response to U46619 challenge is independent of RhoA, reflecting decreased TP association with G12/13 in favor of Gαq. In contrast, hypoxic contractile Ao myocytes polymerize actin modestly and depolymerize to U46619. Both basal APM and the APM response to U46619 are increased in PPHN PA. APM corresponds with increased force generation to U46619 challenge in PPHN PA but not renal arteries.

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